The main purpose of this study is to evaluate the efficacy of selinexor in JAKi-naïve participants with myelofibrosis (MF) and with normal platelet counts or with mild to moderate thrombocytopenia based on spleen volume reduction (SVR). Additional efficacy and safety parameters will also be assessed during the study.

Key Inclusion Criteria:

• A diagnosis of MF or post-ET or post-PV MF according to the 2016 World Health Organization (WHO) classification of MPN, confirmed by the most recent local pathology report
• Measurable splenomegaly during the screening period as demonstrated by spleen volume of greater than or equal to (>=) 450 cubic square centimeter (cm^3) by MRI or CT scan (results from MRI or CT imaging performed within 28 days prior to C1D1 are acceptable)
• DIPSS risk category of intermediate-1 with symptoms, or intermediate-2, or high-risk
• ECOG Performance Status less than or equal to (<=) 2
• Platelet count of greater than or equal to (>=) 50 x 10^9/L without platelet transfusion within 7 days prior to the first dose of selinexor
• Absolute neutrophil count (ANC) >=1.0 × 10^9/L without need for growth factors within 7 days prior to the first dose of selinexor
• Adequate liver function as defined by the following: aspartate transaminase (AST) and alanine transaminase (ALT) <= 2.5 × upper limit normal (ULN) and serum total bilirubin <= 3×ULN
• Calculated creatinine clearance (CrCl) greater than (>) 15 milliliter per minute (mL/min) based on the Cockcroft and Gault formula
• Active symptoms of MF as determined by presence of at least 2 symptoms with an average score >= 5 or total score of >= 12 at screening (at least 5 of 7 consecutive days immediately preceding C1D1) using the MFSAF V4.0
• Must provide bone marrow biopsy samples (samples obtained up to 3 months prior to C1D1 are permitted) at screening and during the study
• Currently not eligible for stem cell transplantation
• Must be willing to complete the MFSAF V4.0 daily during the study for evaluating the symptom response (i.e., TSS50)

Key Exclusion Criteria:

• More than 10% blasts in peripheral blood or bone marrow (accelerated or blast phase)
• Previous treatment with JAK inhibitors for MF
• Previous treatment with selinexor or other XPO1 inhibitors
• Females who are pregnant or lactating
• Prior splenectomy, splenic radiation, or a splenic embolization within 6 months prior to C1D1
• History of myocardial infarction, unstable angina, percutaneous transluminal coronary angioplasty (PTCA), coronary artery bypass graft (CABG), cerebrovascular accident (transient ischemic attack [TIA]), ventricular arrhythmias, congestive heart failure class > 2 per New York Heart Association (NYHA) within 6 months of C1D1
• Unable to tolerate two forms of antiemetics prior to each dose for the first two cycles